Process for microbiologically oxygenating 1-amidoadamantanes

ABSTRACT

A NOVEL METHOD FOR THE INTRODUCTION OF OXYGEN INTO 1-AMINOADAMANTANES BY BICONVERSION BY MEANS OF SPOROTRICHUM SULFURESCENS, RHIZOPUS ARRHIZUS OR CURVULARIA LUNATA TO OBTAIN THE CORRESPONDING OXYGENATED 1AMIDOANDAMANTANES WHICH CAN BE CHEMICALLY CONVERTED TO NOVEL DERIVATIVES THEREOF. THESE NOVEL BIOCONVERSION PRODUCTS AND THEIR DERIVATIVES ARE OF PARTICULAR VALUE AS CENTRAL NERVOUS SYSTEM STIMULANTS.

United States Patent 3,649,453 PROCESS FOR MICROBIOLOGICALLY OXY. GENATING l-AMIDOADAMANTANES Milton E. Herr, Kalamazoo, Herbert C. Murray, Hickory Corners, and Gunther S. Fonkeu, Galesburg, Mich.,

assignors to The Upjohn Company, Kalamazoo, Mich. No Drawing. Continuation-impart of abandoned applications Ser. No. 666,990, Sept. 11, 1967, and Ser. No.

528,346, Feb. 18, 1966. This application Jan. 21, 1970,

Ser. No. 4,782

Int. Cl. G12d 13/00 U.S. Cl. 195-51 17 Claims ABSTRACT OF THE DISCLOSURE A novel method for the introduction of oxygen into l-aminoadamantanes by bioconversion by means of Sporotrichum sulfurescens, Rhizopus arrhizus or Curvalaria lunara to obtain the corresponding oxygenated 1- amidoandamantanes which can be chemically converted to novel derivatives thereof, These novel bioconversion products and their derivatives are of particular value as central nervous system stimulants.

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of application Ser. No. 666,990, filed Sept. 11, 1967 and now abandoned. Application Ser. No. 666,990 is a continuation in part of abandoned application Ser. No. 528,346, filed Feb. 18, 1966.

SUMMARY OF THE INVENTION The products of this invention are represented by the following structural formulae:

and

methyl; X is hydrogen, hydroxy, keto or acyloxy; Y is hydroxy, keto or acyloxy; W is hydroxy or acyloxy; and the wavy lines (I) appearing at the 4- and 6-p0sitions indicate the 0: (alpha) configuration, the [3 (beta) configuration and mixtures thereof, when the attached substituent is hydroxy or a derivative thereof.

In this application the substituents at the 4- and 6-positions of the adamantane ring will be referred to as on when trans to the C nitrogen bond and B when cis to the C nitrogen bond.

The term alkyl means an alkyl group of from 1 to 18 carbon atoms, inclusive such as methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, decyl, dodecyl, octadecyl and isomeric forms thereof. The term cycloalkylmethyl means the radical, CH 'R wherein R is a cycloalkyl radical of 3 to 6 carbon atoms, inclusive, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term cycloalkyl means the residue of a cycloalkane containing from 5 to 15 carbon atoms, inclusive, such as oyclopentyl, cyclooctyl, cyclododecyl and cyclotetradecyl. The term aryl means an aryl radical containing from 6 to 12 carbon atoms, inclusive, such as phenyl, tolyl, xylyl, naphthyl and biphenyl. The term aralkyl means an aralkyl radical of from 7 to 13 carbon atoms, inclusive, such as benzyl, phenethyl, phenylpropyl, benzhydryl, naphthylmethyl and O-carboxylbenzyl. The term acyloxy means a substituent in which the acyl radical is that of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid of from 1 to 18 carbon atoms, inclusive. Examples of acids from which such acyl groups are derived are: saturated and unsaturated aliphatic acids and aromatic acids such as acetic, propionic, butyric, isobutyric, tert.-butylacetic, valeric, isovaleric, caproic, caprylic, decanoic, dodecanoic, acrylic, crotonic, hexynoic, heptynoic, octynoic, cyclobutanecarboxylic, cyclopentanecarboxylic, cyclopentenecarboxylic, cyclohexanecarboxylic, dimethylcyclohexanecarboxylic, benzoic, toluic, naphthoic, ethylbenzoic, phenylacetic, naphthaleneacetic, phenylvaleric, cinnamic, phenylpropiolic, phenylpropionic, p-butoxyphenylpropionic, succinic, glutaric, dimethylglutaric, maleic, cyclopentylpropionic, myristic, palrnitic and stearic acids.

The term novel compounds of this invention as used throughout the specification embraces compounds represented by Formulae 1, 2, 3 and 4 above, including the pharmacologically acceptable acid addition salts of the basic compounds of Formulae 3 and 4, such as, sulfuric, hydrochloric, nitric, phosphoric, lactic, benzoic, methanesulfonic, p-toluenesulfonic, salicyclic, acetic, propionic, maleic, malic, tartaric, citric, cyclohexanesulfamic, succinic, nicotinic and ascorbic acids.

The novel compounds of this invention are central nervous system stimulants. They are mood elevators and psychic energizers and are useful in the treatment of mental health conditions.

The novel compounds of this invention are useful in the treatment of animals and birds, and are particularly useful in the treatment of humans and valuable d0- mestic animals. They can be administered as active ingredients in conventional pharmaceutical forms such as tablets, capsules, elixirs, injectable solutions and suspensions.

Additionally, the free bases of Formulae 3 and 4 form salts with fluosilicic acid which are useful as mothproofing agents in accord with U.S. Pats. 1,915,334 and 2,075,359. The free bases of Formulae 3 and 4 also form salts with thiocyanic acid which condense with formaldehyde to form resinous materials useful as pickling inhibitors according to U.S. Pats. 2,425,320 and 2,606,155.

The microbiological process of this invention is repre- X1 LJH wherein R and Z have the meanings hereinbefore given and X is hydrogen or hydroxy.

The microbiological process of this invention comprises subjecting a l-amidoadamatane (I) to the oxygenating activity of a microorganism of the species Spororrz'chum sulfurescens, Curvularia Iunata or Rhizopus arrhizus to obtain the corresponding 1-amidoadamantan-4-ols and 1- amidoadamantan-3-ols of Formulae 11A and 11B. The genera Sporotrichum and Curvularia belongs to the family Moniliaceae of the order Moniliales of the class Deuteromycetes. The genus Rhizopus belongs to the fam ily M-ucoraceae of the order Mucorales of the' class Phycomycetes.

The typical strains preferred for the practice of this invention are Sporotrichum sulfurescens, Collection No. ATCC 7159; Curvularia lunaza, Collection No. ATCC 12017; and Rhizopus arrhizus, Collection No. ATCC 11145, available fiom the American Type Culture Collection (ATCC), Washington, DC It is to be understood that other strains of these microorganisms are suitable for the practice of this invention.

' The starting materials (I) for the microbiological process of this invention are either known in the art, See British Pat. No. 1,006,885, or can be prepared in accordance with known methods.

The starting materials of Formula I wherein R is hydrogen and Z has the meaning hereinbefore given are prepared from l-aminoadamantane hydrochloride as disclosed in Preparations 1, 2 and 3 herein. For example, 1- aminoadamantane hydrochloride is treated with a base, such as sodium hydroxide to release the free amine, followed by treatment with the anhydride or acid halide of a monobasic hydrocarbon carboxylic acid, for example, a monobasic hydrocarbon carboxylic acid hereinbefore listed under the definition of Z, above, to obtain the corresponding l-acylarnidoadamantanes.

The starting materials of Formula I wherein R is alkyl, cycloalkyl, aryl or aralkyl and Z has the meaning hereinbefore given, are prepared by reacting l-aminoadamantane with the appropriate alkyl, cycloalkyl, aryl or aralkyl halide, in accordance with the procedure disclosed in British Pat. No. 1,006,885 (Examples 2-17), for example the halides of the alkyl, cycloalkyl aryl and aralkyl radicals hereinbefore listed, such as methyl iodide, ethyI bromide, pentyl bromide, decyl bromide, dodecyl bromide, octadecyl bromide, cyclopentyl bromide, cyclooctyl bromide, cyclododecyl iodide, cyclopentadecyl bromide, phenyl bromide, 1- or Z-naphthyl bromide, xylyl bromide, 4- biphenyl bromide, phenylethyl chloride, benzyl bromide etc., to obtain the corresponding l-substituted alkyl, cycloalkyl, aryl or aralkyl aminoadamantane followed by m acylation using the Well known Schothen-Baumann reaction, for example, using an acid halide of a monobasic hydrocarbon carboxylic acid, for example one of the acids hereinbefore listed under the definition of Z, above, in the presence of an aqueous base, such as sodium hydroxide to obtain the desired starting materials of Formula I, wherein R is alkyl, cycloalkyl, aryl or aralkyl as hereinbefore defined and Z has the meanings hereinbefore given.

Alternatively the starting materials of Formula I Wherein R is an alkyl radical of 2 to 18 carbon atoms, or aralkyl as hereinbefore defined and Z has the meanings herein before given are prepared from the l-acylamidoadamantanes of Formula I, wherein R is hydrogen and 2 has the meaning hereinbefore given by reducing the acyl radical with a metal hydride, such as lithium aluminum hydride, to obtain the corresponding alkyl and aralkyl substituted l-aminoadamantanes, followed by acylation with the desired monobasic hydrocarbon carboxylic acid halide using the Schothen-Baumann procedure hereinbefore described.

The operational conditions and reaction procedures for bioconversion process of this invention are advantageous: 1y those known in the art of bioconversion as illustrated in Murray et al., US. Pats. 2,602,769 and 2,735,800, utilizing the oxygenating activity of the microorganism Sporotrichum sulfurercens, Curvularr'a lunata or Rhizopus arrhizus.

In the practice of this invention, the bioconversion can be eifected by a growing or resting culture of the microorganism or by spores, washed cells or enzymes of the microorganism.

Culture of the microorganism for the purpose and practice of this invention is in or on a medium favorable to its development. Sources of nitrogen and carbon should be present in the culture medium and an adequate sterile air supply should be maintained during the conversion, for example, by the conventional techniques of exposing a large surface of the medium or by passing air through a submerged culture.

Nitrogen in assimilable form can be provided by sources normally employed in such processes, suchas corn steep liquor, soybean meal, yeast extracts, pcptone, soluble or insoluble vegetable or animal protein, lactalbumin, casein, whey, distillers solubles, amino acids, nitrates and ammonium compounds, such as ammonium tartrate, nitrate, sulfate and the like. I

Available carbon can also be provided by sources normally used in bioconversions such as carbohydrates, e.g., glucose, fructose, sucrose, lactose, maltose, dextrines, starches; meat extracts, peptones, amino acids, proteins fatty acids, glycerol, whey and the like. These materials may be used either in a purified state or as concentrates such as whey concentrate, corn steep liquor, grain mashes, and the like, or as mixtures of the above. Many of the above sources of carbon can also serve as'a source of nitrogen. 1 A

The medium can desirably have a pH before inoculation of between about 4 to about 7 through a higher or lower pH can be used. A temperature between about 25 to 32 C. is preferred for growth of the microorganism but higher or lower temperatures within a relatively Wide range are suitable. a

The substrate (I) can be added to the culture during the growth period of the microorganism as a, single feed or by gradual addition during the conversion period, or it can be added to the medium before or after sterilization or inoculation making appropriate adjustments foreliects of pH and/or temperature upon the stability of. the substrate used. The preferred, but not limiting, range of concentration of the substrate in the culture medium is about 0.1 to 10 grams per liter. The substrate is added to the medium in any suitable manner, especially one which promotes a large surface contact of the substrate tothe oxidizing activity of the microorganism for example by dissolving the substrate in an organic solvent and mixing the solution thoroughly with the medium or by adding to the medium finely comminuted particles of the substrate, e.g., micronized particles, preferably 90% by weight smaller than 20 microns, either as a dry powder or, preferably for mechanical reasons, as an aqueous suspension. In preparing the aqueous suspension, the use of dispersingor suspending agents is advantageous. Dispersing agents can also be added to the medium.

The temperature during the fermentation can be the same as that found suitable for growth of the microorganism. It need be maintained only Within such range as supports life, active growth or the enzyme activity of the microorganism, the range of 20 to 35 C. is preferred. A pH of about 4 to 8 is generally preferred for growth of the microorganism during the bioconversion but for acid-sensitive substrates, the pH should be above 7 during the fermentation. Aeration can be effected by surface culture or preferably under submerged fermentation conditions, in accordance with methods well known in the art. The time required for oxygenation by the enzymatic system of the microorganism employed can vary considerably. The range of about 2 to 120 hours is practical but not limiting; 72 hours is generally satisfactory. The progress of the bioconversion and its completion are conveniently determined by paper-strip chromatography, vapor-phase chromatography of thinfilm chromatography (Haftman, Chromatography (1961) Reinhold Publishing Co., New York, New York).

Alternatively, the oxygenation of the selected substrate can be effected under aerobic conditions by subjecting it to the oxygenating action of oxygenating enzyme isolated from the microorganism, to the action of spores of the microorganism, and to the action of isolated cells of the microorganism. Isolated enzyme preparations can be prepared in accordance with the general procedure disclosed by Zuidweg et al., Biochim. Biophy. Acts, 58, 131-133 (1962). Oxygenation can be effected with spores in accordance with the general process disclosed in US. Pats. 3,031,379 and 3,031,382. The separation of washed cells from the fermentation medium is well known in the art, see for example, US. Pat. 2,831,789.

The term oxygenating activity as used throughout this specification means the enzymatic action of a growing or resting culture of the microorganism or of spores, washed cells or isolated enzymes of the microorganism, which effects introduction of oxygen in the molecule of the substrate under aerobic fermentation conditions.

After completion of the fermentation, the resulting oxygenated products HA and HE are recovered from the fermentation beer by conventional methods. For example, the whole beer can be extracted with a Water-immiscible organic solvent such as methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, trichloroethylene, ether, amyl acetate, benzene, and the like or the beer and mycelia can be separated by conventional methods such as centrifugation or filtration, and then separately extracted with suitable solvents. The mycelia can be extracted with either water-miscible or water-immiscible solvents or in cases where little or no product is contained in the mycelium, it can be merely washed with Water and the wash water added to the beer filtrate. The beer, free of mycelia, can then be extracted with waterimmiscible solvents such as those listed above. The extracts are combined, dried over a drying agent such as anhydrous sodium sulfate, and the solvent removed by conventional methods such as evaporation or distillation at atmospheric or reduced pressure.

Alternatively, the products can be adsorbed from the beer on granular charcoal and the products eluted with a polar organic solvent such as methanol, ethanol, acetone, ethyl acetate, and the like.

The oxygenated products HA and HE obtained by either the extraction or elution procedures can be isolated and further purified by conventional methods, e.g., chromatography and/or crystallization, and the like.

The l-amidoadamantanla-ols, l-amidoadamantane- 4ot,6oc-di018 and l-amidoadamantan-B-ols of Formulae HA and HE, respectively, can be converted to the other compounds of this invention in accordance with the following reaction schemes:

(um) u 2 (IXA) o or acyloxy, as hereinbefore defined, X is hydrogen or and Y is hydroxy or acyloxy, as hereinbefore defined.

The 1-amidoadamantan-4-ols and l-amidoadamantane- 4,6-diols of Formula IIA can be oxidized to obtain the corresponding l-amidoadamantanl-ones and l-amidoadamantane-4,6-diones of Formula IVA in accordance with methods known in the art for oxidizing secondary hydroxy groups to ketones, for example, Fieser and Fieser, Natural Products Related to Phenanthrene, 3rd ed., pages 127-129, 193 and 194, Reinhold Publishing Corporation, New York, NY. Thus, the selected compound of Formula IIA is dissolved in an inert organic solvent such as acetone, benzene, methylene chloride, t-butanol, and the like, and then oxidized with aqueous chromic acid, potassium permanganate, t-butyl hypochlorite or like oxidizing agents to convert the hydroxy group to keto. The l-amidoadamantan-4-ones and 1 amidoadamantane 4,6 diones (I VA) thus obtained, can be recovered from the reaction mixture and purified by conventional methods. For example, extraction with an organic solvent, e.g., methylene chloride followed by recrystallization from a suitable organic solvent, e.g., acetone, benzene, methylene chloride and the like.

The 1-amidoadamantan-4-ols (IIA), the l-arnidoadamantan-4-ones (IVA) and the l-amidoadamantan-3-ols (IIB) can be converted to 1-aminoadamantan-4-ol IIIA), 1-aminoadamantan-4-one (VA), and l-aminoadamantan- 3-ol (IIIB), respectively, in accordance with methods known in the art, for example, Chem. Ber. 93, 229 (1960) which shows the hydrolysis of l-acetoadamantane to 1- aminoadamantane and preparation of the hydrochloride acid addition salt. The compounds of Formulae IIA, IVA and HE are preferably hydrolyzed with an aqueous strong base, such as sodium or potassium. hydroxide at reflux temperature until hydrolysis is complete. The free amines thus obtained are recovered from the reaction mixture by extraction with a suitable organic solvent such as ether, methylene chloride, benzene, hexane, mixtures of these solvents, and the like. The free amine can be further purified by crystallization from a solvent such as ether, ether hexane, benzene, and the like. Alternatively, the hydrolysis can be carried out using a strong acid. In these instances the acid addition salt of the amine is obtained.

The l-amidoadamantanols of the Formulae IIA and IIB can in some instances be reduced directly to the compounds of Formulae VIIA and VIB, respectively, by the use of known methods, for example, using lithium aluminum hydride. In cases where their reduction does not proceed due to complexing of the free hydroxyl group or groups of the starting adamantanol with the reducing agent, the compounds of Formulae HA and 113 can be reacted with a hydroxyl protecting agent, such as dihydropyrane or an acylating agent to obtain the corresponding tetrahydropyranyl ether or corresponding acyl derivative ofFormulae VIA and IV B, respectively. Thus, the selected hydroxy-1-amidoadamantane is reacted with dihydropyran in the presence of an acid catalyst such as boron trifiuoride etherate, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, and the like. Advantageously, the reaction is carried out in the presence of an organic solvent, such as ether, benzene, and the like. The reaction is carried out at temperatures of from 0 to 0, with a temperature of about 25 C. being preferred. The-'acyl derivatives are prepared in'the same manner-as hereinafter described. Y i

The tetrahydropyranyl ether derivatives of thecompounds of Formulae 'VIA and IVB can then be reduced in accordance with methods known in the art for reducing amides to amines to obtain the corresponding l-aminoadamantane tetrahydropyranyl ethers of Formulae VI-I-A and VB, respectively. The reduction is preferably carried out using lithium aluminum hydride as the reducing-agent. The reduction reaction is carried out in the presence of "an inert organic solvent such as ether, tetrahydrofuran, benzene, diglyme, combination thereof and the like. The reduction reaction is preferably conducted at reflux ternperature and a period of about 1 to about 4 hours is generally sufiicient for completion of the reaction.

The removal of the tetrahydropyranyl ether group is carried out by treating the compounds of Formulae'VIIA and VB with an acid in the presence of an organic solvent to obtain the compounds of Formulae VIIIA and VIB respectively, as acid addition salts of the acid used. Preferably the acid is a mineral acid, such as hydrochloric, hydrobromic, sulfuric acids, and the like. Suitable solvents are acetone-water, methanol-water, ethanol-water, dimethsulfoxide-water, dimethylformamide-water,' and the like. The reaction is conveniently carried out at'temperatures of about 10 C. to the reflux temperature-of the reaction mixture until hydrolysis is complete. The acid addition salts of the compounds of Formulae VIIIA and VIB, thus obtained are recovered from the reaction mixture and purified by conventional methods, or the amine salt can be treated with a base such as sodium or potassium hydroxide and the free amine can be recovered from the reaction mixture by the similar conventional methods, such as extraction with a suitable organic solvent followed by crystallization.

Alternatively the acylates of Formulae VIA and IVB can be reduced directly to the compounds of Formulae VIIIA and VIB, respectively, as hereinbefore described for the dihydropyranyl ether derivatives, thus avoiding the hydrolysis step since the acyl radical is removed during the reduction.

The 1-amidoadamantanones of Formulae IVA and VA can be selectively reduced at the keto group(s) by methods known in the art, for example, using sodium or potassium borohydride to obtain a mixture of a and [3 forms of the corresponding l-amjdoadamantanols of Formula VIIIA, which can be separated by conventional methods such as chromatography, crystallization and the like. Alternatively, the compounds of Formula IVA can also be reduced at both the keto group(s) and the amido group by known methods, for example, using lithium aluminum hydride to obtain a mixture of a and [3 forms of the compounds of Formula VIHA, wherein R is hydrogen. These cc and t9 isomers can be separated and purified by conventional methods, such as chromatography, crystallization, and the like.

The compounds of Formula VIIIA, thus obtained can be oxidized using an Oppenauer oxidation, for example, using a ketone, such as acetone or cyclohexanone and an aluminum alkoxide, such as aluminum isopropoxide in an organic solvent, e.g., benzene or toluene to obtain the corresponding 1-aminoadamantan-4-ones and l-amidoadamantane-4,6-diones of Formula IXA. The compounds of Formula IXA are recovered from the reaction mixture by conventional methods, for example, first neutralizing or acidifying the reaction mixture with a mineral acid, e.g., hydrochloric acid extracting the mixture thus obtained with a suitable organic solvent, e.g., benzene, toluene, ether, methylene chloride and the like, to remove organic impurities. The aqueous layer is then made basic, for example, with sodium or potassium hydroxide and the product IXA is extracted with ether or other suitable organic solvent, the solvent is removed by evaporation or distillation and the product purified by crystallization.

Alternatively, the compounds of Formula IXA can be obtained directly from the compounds of Formula IVA by protecting the keto group with a cyclic alkylene ketal in accordance with methods known in the art and then following the procedure described hereinabove for reducing the compounds of Formula VIA to VIIA. The ketal group is removed by acid hydrolysis in the same manner as described hereinabove for hydrolysis of the tetrahydropyranyl ether group.

The free amines of Formulae IIIA, VA, VIIIA, IXA, IIIB and VIB of this invention can be converted by known methods to their pharmacologically acceptable acid addition salts by treating the selected amine with the appropriate acid, for example, those acids hereinbefore listed, in the presence of an inert solvent such as methanol, ethanol, diethyl ether, ethyl acetate, and the like.

The compounds of Formulae IIA, IIB, VIIIA and VIB can be converted to the corresponding acyl derivatives thereof in accordance with methods known in the art for acylating secondary and tertiary hydroxy groups. For example, the compounds of Formula IIA are acylated at the 4-position by reaction with the appropriate acid anhydried or acid halide, by reaction with the appropriate ester or by reaction with the appropriate acid in the presence of an esterification catalyst, for example, p-toluenesulfonyl chloride, trifiuoroacetic anhydride, p-toluenesulfonic acid, trifiuoroacetic acid, sulfuric acid, and the like. The tertiary hydroxy compounds of Formula 11B are acylated using more vigorous acylation procedures, for example, the selected l-amidodamanta-3-ol (HE) is heated with the selected acid anhydride in the presence of an alkali earth carbonate, e.g., calcium carbonate until the reaction is complete. Suitable acylating agents are organic carboxylic acids, particularly hydrocarbon carboxylic acids containing from 1 to 12 carbon atoms, such as those hereinbefore listed, or acid anhydrides or acid halides thereof.

The 4a,6a-diols of Formulae HA, IIIA, and VIIIA can be converted to certain cyclic addition compounds, such as sulfites, carbonates and phosphates and the like, in accordance with methods known in the art. For example, the selected 4a,6ozdiol can be reacted with thionyl chloride to give the corresponding cyclic sulfite, with phosgene to give the corresponding cyclic carbonate, or with phosphorous oxychloride to give the corresponding cyclic phosphate. These cyclic addition compounds, like the parent compounds are useful as central nervous system stimulants. They have the additional advantage in that they can be used as slow releasing agents which given the parent compounds on hydrolysis in vivo.

The compounds of Formulae IVA, VA, and IXA, can be converted to their common carbonyl derivatives such as oximes, hydrazones, semicarbazones, cyclic alkylene ketals and the like in accordance with methods well known in the art. For example, the carbonyl groups can be ketalized by reacting the selected compound with an alkanediol selected from the group of vicinal alkane-l,2-diols and alkane-1,3-diols containing up to and including 8 carbon atoms, e.g., ethylene, propylene, trimethylene, 2,3-butylene, 2,4-pentylene, 4-methyl-l,2-pentylene, 1,3-hexylene, 1,2-heptylene, 3,4-hepty1ene, 1,3-octylene, and the like, preferably in an organic solvent such as benzene, toluene, xylene, methylene chloride, and the like and in the presence of an acid catalyst such as p-toluenesulfonic acid. The reaction is conducted at a temperature between about 20 and about 200 C., preferably between about 40 and about 150 C. The time required for the reaction is not critical and may be varied between about 1 to 48 hours, depending on the temperature. The ketonic derivatives, the oximes, etc., can be prepared in accordance With known methods as described in identification of Organic Compounds, Shriner and Fuson, John Wiley and Sons, Inc., New York, N.Y.

The acylates, cyclic alkylene ketals, oximes and other ketonic derivatives of the compounds of this invention 10 can, if desired, be hydrolyzed in accordance with methods known in the art, for example, using aqueous acids or bases to give the corresponding free-hydroxy and freeketo compounds.

DETAILED DESCRIPTION The following preparations and examples are intended to illustrate the process and products of this invention. The examples are for the purpose of illustrating the best mode contemplated of carrying out the invention and to supplement the foregoing disclosure of the invention with additional descriptions of the manner and process of carrying out the invention so as to further enable workers skilled in the art to do so, but they are not to be construed as limiting.

Preparation 1 1 -benzamidoadamantane Two grams of l-aminoadamantane hydrochloride, 20 ml. of 10% aqueous sodium hydroxide and 2.0 ml. of benzoyl chloride were vigorously mixed for a period of about 20 minutes; an additional 1.0 ml. of benzoyl chloride was then added and stirring was continued at room temperature (about 25 C.) for an additional period of about 1 hour. The precipitated product thus obtained was recovered by filtration washed with water and dried to give 2.65 g. of l-benzamidoadamantane, MP. 144- 146 C. An analytical sample prepared by recrystallization of the product from aqueous acetone gave 1- benzamidoadamantane; M.P. 148-149 C.

In like manner following the procedure of Preparation 1, above, but substituting other monobasic hydrocarbon carboxylic acid halides such as those of the acids hereinbefore listed, in place of benzoyl chloride is productive of the corresponding l-amidoadamantanes of Formula I for example those prepared and listed in Preparation 2, below.

PREPARATION 2 1 -acetamid0udamantane A mixture of 2 g. of l-aminoadamantane and 1.0 ml. of acetic anhydride is heated at 30100 C. for about 60 minutes and then 50 ml. of water is added and stirring is continued for an additional period of about 1 hour. The reaction mixture is extracted with ether and the ether layer is separated, washed with dilute aqueous sodium hydroxide solution, water, dried on anhydrous sodium sulfate and the ether is removed by evaporation. The residue thus obtained is recrystallized from ether to give l-acetamidoadamantane. i

In the same manner substituting acetyl chloride for acetic anhydride in Preparation 2 is productive of 1- acetamidoadamantane.

In like manner substituting in the procedure of Preparation 2 the acid anhydrides or acid halides of other monobasic hydrocarbon carboxylic acids, such as the anhydrides or halides of those acids hereinbefore listed, in place of acetic anhydride is productive of the corresponding 1- arnidoadamantanes of Formula I. For example using the following acid anhydrides and acid halides:

propionic anhydride,

butyric anhydride,

valeric anhydride,

caproic anhydride,

decanoic anhydride, dodecanoic anhydride, cyclopropanacarbonyl chloride, cyclohexanecarbonyl chloride, toluyl chloride,

naphthoyl chloride, p-ethylbenzoyl chloride, phanylacetyl chloride, stearoyl chloride,

andthe like, there is respectively obtained 1 -pr'opi onamidoad amantane,

l butyramid'oadamantane, l-valeramidoadamantane, 1-hexanamidoadamantane,j ldecauamidoadamantane, I-dodecanamidoadarnantane, l-"cyclopropanecarboxamidoadamantane, 1-cyclohexanecarboxamidoadamantane, l-toluarnidoadamantane, l-napthamidoadarnantane, l-(p-ethylbenzamido) adamantane, l-phenylacetamidoadamantane, l-stearamidoadamantane,

and the like.

PREPARATION 3 1 -formamz'doadamantane PREPARATION 4 N methyl-1 -benzam idoadamantane Seventy grams of l-formamidoadamantane dissolved in 700 ml. of dry tetrahydrofuran was added with stirring to a suspension of 40 g. of lithium aluminum hydride in 2000 ml. of dry ether. The mixture was then heated at reflux for four hours. After chilling in an ice-acetone bath 150 ml. of water was cautiously added to the stirred mixture. The solids were removed by filtration and washed well with ether. The combined filtrate and wash was dried over magnesium sulfate and treated with ether containing one equivalent of hydrogen chloride. The solid salt thus obtained was recovered by filtration, washed with ether and dried to give 66.0 g. of N methyl 1- adamantanamide hydrochloride; M.P. 248-250- C. The analytical sample recrystallized from methanol-methyl ethyl ketone melted at 250 C.

Analysis.-Calcd. for C N NCl (percent): C, 65.49; H, 9.99; N, 6.94; Cl, 17.58. Found (percent): C. 65.32; H, 10.25; N, 686; C1, 17.55.

A mixture of 25.0 g. of the N-methyl-l-adamantam amine hydrochloride, 250 ml. of 10% sodium hydroxide solution, and 25.0 ml. of benzoyl chloride chilled at was stirred vigorously for 2 hours. The product was recovered by filtration, washed with water, dried to give 28.12 g. of N-methyl-l-benzamidoadamantane, M.P. 117- 119' C.; an analytical sample recrystallized from aqueous acetone melted at l17-119 C.

Analysis.-Calcd. for C ,,H NO (percent): C, 80.25; H, 8.61; N, 5.20. Found (percent): C, 80.03; H, 8.69; N, 5.30.

PREPARATION N-methyl-I -acetamid0adamantane A solution of 6.5 g. of N-methyl-l-adamantanamine hydrochloride in 100 ml. of water was treated dropwise with a slight excess of 50% aqueous sodium hydroxide solution. The precipitated free base was recovered by filtration, washed with water, and dried; yield, 5.49 g.

The free base was dissolved in 25 ml. of pyridine; five milliliters of acetic anhydride was allowed to stand at 25 C. for 56 hours. After diluting with 100 ml. of water and chilling the product was recovered, washed well with water and dried to give 3.65 g. of N-methyl-l-acetamidoadamantane; M.P. l23124 C.

12 PREPARATION 6 r N -methyl-1 -cycl0hexylcarboramidoadamantape -A mixture of 20.0 g. of N-methyl-l-adarnantanamine hydrochloride and 200 ml. of 10%. aqueous sodium hydroxide solution was chilled at 5 and treated with 20 ml. of cyclohexane carbonyl chloride during'120 minutes with vigorous stirring. The mixture was extracted with methylene chloride, the extract washed with water, dilute hydrochloric acid, 5% sodium bicarbonate solution and dried over sodium sulfate. Evaporation of the-solvent gave 20.20 g. of N-methyl-l-cyclohexylcarboxamidoadamantane; an analytical sample recrystallized from aqueous methanol malted at 91-93 C. 1

Analysis.--Calcd. for C H NO (percent): C, 78.49; H, 10.61; N, 5.09. Found-(percent): C, 78.29; H, 10.90; N, 5.04.

PREPARATION 7 1-phemylacetamidoadamantane' A mixture of 20.0 g. of 1-adarnantanamine hydrochloride, 40 ml. of 50% aqueous sodium hydroxide solution, 160 g. of ice and 20 ml. of phenylacetylchloride was stirred vigorously for 1 hour and allowed to stand for several hours. The product was recovered by filtration and washed with water and air dried to give 20.23 g. of 1-phenylacetamidoadamantane, M.P. 176179 C.; an analytical sample recrystallized from acetone melted at 181- 183 C.

Analysis.Calcd. for C H NO (percent): C, 80.25; H, 8.61; N, 5.20. Found (percent): C, 79.89; H, 8.88; N, 5.04.

PREPARATION 8 N-] -adamantanephfhalimidinef A mixture of 12.0 g. of N1-adamantylphthalimide and 240 ml. of 1 M borane in tetrahydrofuran was heated at reflux for 2 hours and then concentrated under reduced pressure to remove most of the solvent. Methanol (200 ml.) and 20 ml. of 2 N hydrochloric acid was added and the mixture was concentrated in vacuo to 200 ml., chilled, and the product was recovered by filtration, washed with water, and dried to give 9.884 g. of N-l-adamantanephthalimidine; M.P. 220-221" C.; an analytical sample from methanol melted at 222223 C.

Analysis.Calcd. for C H NO (percent): C, 80.86; H, 7.92; N, 5.24. Found (percent): C, 81.44; H, 7.56; N, 5.31.

EXAMPLE 1 Oxygenation of l-acemmidoadamantane A medium was prepared of 40 g. of cornsteep liquor (60% solids), 20 g. of commercial dextrose diluted to 1 liter with tap water and adjusted to a pH of between 4.8 and 5.0. One ml. of UCON LB 625 (Union Carbide) was added as an antifoarn agent. One hundred liters of this medium was sterilized and inoculated with 72-hour vegetative growth of Sporotrichum sulfurescens, ATCC 7159, and incubated at about 28 C. with aeration at about 5 l. per minute and stirring at about 300 rpm. After about 43 hours, or when a moderate to heavy growth of mycelium was apparent, 250 ml. of ULRAWET DS 30 (A-RCO Chemical Co.) and a solution of 55 g. of l-acetamidoadamantane in about 500 ml. of N,N-dimethylformamide was added to the fermentation. After an additional 72- hour period of incubation, 1500 g. of diatornaceous earth (Celite) was added and the beer and myceliu-m were separated by filtration.

The beer thus obtained, was passed over a carbon column containing 3 kilograms of granular carbon (Pittsburg Chemical Co.). The column was prepared by heating the granular carbon in deionized water at -90 C., cooling it and wet packing it into the column.

The column was eluted with 50 l. of methanol. The eluate containing the desired products was concentrated under reduced pressure to dryness. The residue was well stirred with 400 ml. of methanol and filtered to remove insoluble debris. The methanol filtrate was thoroughly mixed with 500 g. of silica gel (.050.20 millimicron) and air dried on a tray. The air dried material was then added to the top of a wet packed (ethyl acetate) silica gel column. The column was first eluted with 6 liters of ethyl acetate and then with ethyl acetate containing increasing proportions of methanol, 2% to 18%. One liter fractions were collected.

The fractions containing 1-acetarnidoadamantan-4a-ol, determined by thin layer chromatographic analysis, were combined and the solvent was removed by distillation at reduced pressure. The residue thus obtained was recrystallized from acetone giving 19.19 g. of l-acetamidoadamantan-4a-ol, M.P. 173175 C., infrared and N.M.R. analysis confirmed the structure:

Analysis.Calcd. for C H NO (percent): C, 68.86; H, 9.15; N, 6.69. Found (percent): C, 68.87; H, 9.22; N, 6.83.

The fractions containing 1-acetamidoadamantan3-ol, determined by thin layer chromatography, were likewise combined, the solvent removed and the residue recrystallized from acetone to give 5.08 g. of l-acetamidoadamantan-3-ol, M.P. 223-225 C., infrared and N.M.R. analysis confirmed the structure:

Analysis.-Calcd. for C H NO (percent): C, 68.86; H, 9.15; N, 6.69. Found (percent): C, 69.00; H, 9.11; N, 6.82.

The other fractions which contained mixtures of the desired products and the mother liquors from the above recrystallizations were rechromatographed over silica gel giving and additional 4.23 g. of 1 acetamidoadamantan- 4a-ol and an additional 2.30 g. of 1 acetamidoadamantan- 3-ol.

In the same manner Rhizopus arrhizus, ATCC 11145 or Curvularia lunaza, ATCC 12017, can be used in place of Sporotrichum sulfurescens to obtain 1 acetamidoadamantan-3-ol and 1-acetamidoadamantan-4a-ol.

In the same manner following the procedure of Example 1, other 1 amidoadamantanes of Formula I can be substituted as the substrate in place of l-acetamidoadamantane to obtain the corresponding l-amidoadamantan-4-o1s and l-amidoadamantan-B-ols of Formulae HA and HE, respectively.

The following conversions are representative:

l-forrnamidoadamantane to 1-formamidoadamantan-4a 01 and l-formamidoadamantan-B-ol; l-benzamidoadamantane to 1-benzamidoadamantan-4a-ol and 1-benzamidoadamantan-3-ol; l-propionamidoadamantane to l-propionamidoadamantan-4a-ol and 1-propionamidoadamantan-3-ol; l-butyramidoadamantane to 1-butyramidoadamantan-4a- 01 and 1-butyramidoadamantan-3-ol; l-valeramidoadamantane to 1-valeramidoadamantan-4a- 01 and 1-valeramidoadamantan-3-ol; l-hexanamidoadamantane to l-hexanamidoadamantan- 4a-ol and 1-hexanamidoadamantan-3-01; l-decanamidoadamantane to l-decanamidoadamantan- 4a-01 and 1-decanamidoadamantan-3-ol; l-dodecanamidoadamantane to ll-dodecanamidoadamantan-4a-ol and 1-dodecanamidoadamantan-3-ol; 1-cyclopropanecarboxamidoadamantane to l-cyclopropanecarboxamidoadamantanla-ol and l-cyclopropanecarboxamidoadamantan-3-ol; 1-cyclohexanecarboxarnidoadamantane to l-cyclohexanecarboxamidoadamantan-4a-ol and l-cyclohexanecarboxamidoadamantan-3-ol; l-toluamidoadamantane to 1-toluamidoadamantan-4a-ol and l-toluamidoadamantan-3-01; l-naphthamidoadamantane to l-naphthamidoadamantan- 41-01 and 1-naphthamidoadamantan-3-ol; l-(p-ethylbenzamido)adamantane to l-(p-ethylbenzamido)-adamantan-4a-ol and l-(p-ethylbenzamido) adamantan-3-ol;

14 1-(phenylacetamido)adamantane to l-(phenylacetamido)adamantan-4u-ol and l-(phenylacetamido) adamantan-S-ol; and l-stearamidoadamantane to l-steararnidoadamantan-4a- 01 and .1-stearamidoadamantan-3-01.

EXAMPLE 2 Oxygenation of .l-benzamidaadaman tane Ten liters of sterilized medium of the same composition as used in Example 1 was inoculated with 72-hour vegetative growth of Sporotrichum sulfurescens, ATCC 7159, and incubated at about 28 C. with aeration at 0.5 l. per minute and stirring at 300 rpm. After 24 to 48 hours, or when a moderate to heavy growth of mycelium was apparent, a solution of 25 ml. of (Ultrawet DS 30 and 2 g. of l-benzarnidoadamantane in 20 ml. of N,N- dimethylformamide was added to the fermentation. After an additional 72-hour period of incubation, the beer and mycelium were extracted with 101. of methylene chloride. The extracts were filtered, dried over sodium sulfate, concentrated to 75 ml. and chromatographed on synthetic magnesium silicate (Florisil). Elution with hexanes (Skellysolve B) containing increasing proportions of acetone gave 0.51 g. of 1-benzamidoadamantan-4u-ol. The crude product thus obtained was recrystallized from acetonehexanes (Skellysolve B) giving 0.42 g. of l-benzamidoadamantan-4wol, M.P. 178-181 C.

Analysis.-Calcd. for C H NO (percent): C, 75.24; H, 7.80; N, 5.16. Found (percent): C, 75.15; H, 7.71; N, 5.30.

Thin layer chromatographic analysis of the mother liquors showed the presence of 1-benzamidoadamantan- 3-ol.

EXAMPLE 3 Oxygenation of I-acetamz'aoadamantane The bioconversion and extraction procedures of Example 1 were carried out on a smaller scale using 10 liters of sterilized medium of the same composition, 4.0 g. of l-acetamidoadamantane as the substrate and the microorganism Rhizopus arrhizus ATCC 11145. Paper and thin layer chromatographic analysis of the eluates showed the presence of 1-acetamidoadamantan-4-ol and l-acetamidoadamantan-B-ol.

EXAMPLE 4 Oxygenation of I-acetamidoaa'amantane The bioconversion and extraction procedures of Example 1 were carried out on a smaller scale using 10 liters of sterilized medium of the same composition, 4.0 g. of l-acetamidoadamantan as the substrate and the microorganism Curvularia lunata, ATCC 12017. Paper and thin layer chromatographic analysis of the eluates showed the presence of l-acetamidoadamantan-4-ol and l-acetamidoadamantan-3-ol.

EXAMPLE 5 Oxygenation of N-methyl-I-benzamid0adamantane One hundred liters of sterilized medium of the same composition as used in Example 1 was inoculated with 72-hour vegetative growth of Sporotrichuml sulfurescens, ATCC 7159, and incubated at about 28 C. with aeration at 5 l. per minute and stirring at 300 r.p.m. After 24 to 48 hours, or when a moderate to heavy growth of mycelium was apparent, 250 ml. of Ultrawet DS 30 and a solution of 18 g. of N-methyl-l-benzamidoadamantane in about 200 ml. of N,N-dimethylformamide was added to the fermentation. After an additional 72-hour period of incubation, the beer and mycelium were extracted with l. of methylene chloride. The extracts were filtered, dried over sodium sulfate and evaporated to remove the solvent. The residue thus obtained was chromatographed on a column of 700 g. of Florisil. The residue was placed on the column with 850 ml. of methylene chloride fol- 15 lowed by gradient elution in fractions of 350 ml. each with 8.1 of solvent, Skellysolve B hexanes containing increasing proportions of acetone from 10% to 70%. This was followed with 4 l. of hexanes plus 70% acetone and finally 4 l. of acetone.

The fraction residues were examined by infrared and thin layer chromatography. The fractions containing the monohydroxylated product were combined and recrystallized from aqueous acetone to give 2.84 g. of N-methyl- 1-benzamidoadamantan-4a-ol, M.P. 1701'8l C.

Fog 3400, v c= in Nujol Analysis.Calcd. for C H NO (percent): C, 75.75; H, 8.12; N, 4.91. Found (percent): C, 75.77; H, 8.35; N, 4.90.

The fractions containing the dihydroxylated product were combined and recrystallized from aqueous methanol to give 10.39 g. of rN-methyl-l-benzamidoadamantan-4u, Ga-diol, M.P. 223-226 C.

m 3430, 3200, v 1590, 1570 in Nujol Analysis.Calcd. for C H -NO (percent): C, 71.73; H, 7.69; N, 4.65. Found (percent): C, 71.87; H, 8.02; N, 4.81.

EXAMPLE 6 Oxygenation of N-methyl-I-benzamidoadamantan- 4ct-0l The bioconversion and extraction procedures of EX- ample 2 were repeated using 2.0 g. of N-methyl-l-benzamidoadamantan-4a-ol as the substrate. The methylene chloride extracts thus obtained were combined, filtered, dried over sodium sulfate and chromatographed over 150 g. of silica gel. The column was eluted in 50 ml. fractions with ethyl acetate which had been saturated with water. The fractions which contained the dihydroxylated product were pooled and recrystallized from methanolwater to give 0.76 g. of N-methyl-1-benzamidoadamantan- 4a,6u-diol, M.P. 223-226 C. The infrared spectrum and mixed melting point showed the product to be identical to that of the diol described in Example 5, above.

EXAMPLE 7 Oxygenation of N-methyl-I-acetamidoadamantane The bioconversion and extraction procedures of EX- ample 2 were repeated using 2.0 g. of N-methyl-l-acetamidoadamantane as the substrate. The methylene chloride extracts thus obtained were combined, dried over sodium sulfate and evaporated to dryness. The residue thus obtained was dissolved in methylene chloride and chromatographed over 100 g. of Florisil. Elution was by the gradient method in cuts of 100 ml. each using 4 l. of solvent, Skellysolve B hydrocarbons containing increasing proportions of acetone from to 30%. The fractions containing the 4-hydroxylated product, as determined by thin layer chromatography on the fraction residues were combined and recrystallized from acetone-hexane to give 0.717 g. of N-methyl-l-acetamidoadamantan-4a-ol, M.P. 15l-l54 C.

V0,; 3360, made 1610 in Nujol Analysis.Calcd. for C H NO (percent): C, 69.92; H, 9.48; N, 6.27. Found (percent): C, 70.09; H, 9.57; N, 6.36. p

The fractions containing the 3-hydroxylated product, as determined by thin layer chromatography were combined and recrystallized from acetone-hexane to give 0.140 g. of N-methyl-l-acetamidoadamantan3-ol, M.P. 155-456 C.

Arzalysis.Calcd. for C N NO (percent): C, 69.92; H, 9.48; N, 6.27. Found (percent): C, 69.95; H, 9.26; N, 6.24.

16 EXAMPLE 8 Oxygenation of N-meflzyl-I-cyclohexyloarboxamidoadamantane The bioconversion and extraction procedures of EX- ample 2 were repeated using 2.0 g. of N-methyl-1cycl ohexylcarboXamidoadamantane as the substrate.

The methylene chloride extracts thus obtained were chromatographed over 100 g. of Florisil. The column was eluted by the gradient method with 4 l. of solvent, Skellysolve B hydrocarbons containing increasing amounts of acetone from 0 to 40%. Cuts of 110 ml. each were collected and the residues were exami'nedby thin layer chromatography. The fractions containing dihydroxylated products were pooled and recrystallized from acetone to give 0.714 g. of N-methyl-1-cyclohexylcarboxamidoadamantan-4a,-6a-diol, M.P. l-l9l C.

Analysis.--Calcd. for C H NO (percent): C, 70.32; H, 9.51; N, 4.56. Found (percent): C, 70.31; H, 9.51; N, 5.35.

The remaining fractions and mother liquors contained N-methyll-cyclohexylcarboxamidoadamantan 4a-ol.

EXAMPLE 9 Oxygenation of 1-phenylaceramidoadamantane The bioconversion and extraction procedures of EX- ample 2 were repeated using 2.0 g. of N-phenylacetyl-ladamantanamine as the substrate. The methylene chloride extracts thus obtained were combined, dried over sodium sulfate and evaporated to dryness. The residue thus obtained was triturated with 40 ml. of methylene chloride and filtered to obtain 1.05 g. of solid product which was combined with that obtained from the chromatography described below.

The filtrate was placed on a column of g. of Florisil. Elution was by the gradient method 6 l. of solvent, Skellysolve B hydrocarbons plus increasing proportions of acetone from 0 to 60%. Cuts of 55 ml. each were collected. Fraction residues (036g) which were identical with the material obtained by direct isolation were combined with this material (1.41 g.) and recrystallized from acetone after treatment with activated carbon to give l-phenylacetamidoadamantan-4u,6a-diol, M.P. 201202 C.

.105, 3300, WM 1640, 1550 in Nujol Analysis.-Calcd. for C H NO (percent): C, 71.73; H, 7.69; N, 4.65. Found (percent): C, 71.74; H, 7.94; N, 4.62.

Thin layer chromatography showed the presence of l-phenylacetamidoadamantanla-ol in the mother liquors and in the other fraction.

EXAMPLE 10 Oxygenation of N-I-adamamanephthalimide The bioconversion procedure of Example 2 was repeated using 2.0 g. of N-l-adamantanephthalimide as the substrate. The mycelium was removed by filtration and the beer was poured over a column of 300 g. of granular carbon. The column was eluted first with 10 l. of methanol, followed with 5 l. of ethyl acetate, and finally 5 l. of chloroform. Thin layer chromatography showed that the chloroform eluate contained the dihydroxy product. The residue therefrom was chromatographed over 100 g. of Florisil. Elution was by the gradient method with 4 l. of solvent Skellysolve B plus increasing amounts of acetone from 0 to 40%; cuts wereca. ml. each. The fractions containing the dihydroxylated product were recrystallized from acetone-hexane to give 4a,6a-dihydroxy- N-l-adamantanephthalimide, M.P. 2l8220 C.

Analysis-Called. for C H NO (percent): C, 68.99; H, 6.11; N, 4. .7. Found (percent): C, 68.81; H, 6.39; N, 121-.

Thin layer chromatography showed that the other fractions and the mother liquors contained 4ahydroxy-N-1- adamantanephthalimide.

A small amount of a second dihydroxy product, M.P. 229-231 C. was recovered from the higher fractions by recrystillization from acetone-hexane.

Analysis.-Calcd. for C H NO (percent): C, 68.99; H, 6.11; N, 4.47. Found (percent): C, 68.93; H, 6.45; N, 4.51.

EXAMPLE 11 Oxygenation of N-1-adamamanephrhalimidine The bioconversion and extraction procedures of Example 2 were repeated using N-l-adamantanephthalimidine as the substrate. The methylene chloride extracts were evaporated to dryness and the residue was triturated with methanol. The product thus obtained was recrystallized from aqueous acetic acid to give 4u,6a.-dihydroxy-N-1-adamantanephthalimidine, M.P. 278-280 C.

Analysis.CalCd. for C H NO (percent): C, 72.21; H, 7.07; N, 4.68. Found (percent): C, 72.32; H, 7.11; N, 4.83.

EXAMPLE 12 1-acetamid0adamantan-4-0ne A mixture of 2.45 g. of 1-acetmidoadamantan-4u-ol and about 150 ml. of acetone was treated dropwise, while maintaining the temperautre below 40, with chromic acid solution (prepared from 167 g. of chromic anhydride, 230 ml. of concentrated sulfuric acid, and water sufficient to make 1 1.) until a slight excess had been added. The mixture was stirred for five minutes; 5.0 ml. of isopropanol was added and the mixture concentrated under reduced pressure to about one-third volume, diluted with 100 ml. of water, and extracted several times with methylene chloride. The combined extracts were washed with water, dried over sodium sulfate, and concentrated to dryness to give 2.13 g. of 1-acetamidoadamantan-4-one. An analytical sample crystallized from acetone gave 1- acetamidoadamantan-4-one, M.P. 176-178 C.

Analysis.Calcd. for C H NO (percent): C, 69.53; H, 8.27; N, 6.76. Found (percent): C, 69.88; H, 8.51; N, 6.79.

1 EXAMPLE 13 N-methyl-I-benzamidoadamantane-4,6-di0ne Two grams of the N-methyl-l-benzamidoadamantane- 4u,6a-diol dissolved in acetone by heating was treated dropwise with a slight excess of chromic acid solution in the manner described in Example 12, above. The

resulting product was recrystallized from aqueous methanol to give 1.70 g. of N-methyl-l-benzamidoadamantane- 4,6-dione; for spectral and elemental analysis a sample was dried at its melt temperature, 157-160 C. to remove water of crystallization VC=Q 1740, 1700, v =o 1620 in Nujol Analysis.Calcd. for C H NO (percent): C, 72.70; H, 6.44; N, 4.71. Found (percent): C, 72.79; H, 6.82; N, 5.07.

' EXAMPLE 14 N-methyl-1-benzamid0adamantan-4-0ne Seventy milligrams of N-methyl-l-benzamidoadamantan-4a-ol dissolved in ml. of acetone and oxidized with chromic acid by the method described in Example 12, above. The product thus obtained was recrystallized from aqueous acetone to give N-methyl-l-benzamidoadamantan-4-one, M.P. 126127 C.

v 1720, N-C=O 1620 in Nujol Analysis.Calcd. for C H NO' (percent): C, 76.29; H, 7.47; N, 4.94. Found (percent): C, 76.13; H, 7.54; N, 5.07.

EXAMPLE 15 N -m.*ethyl-1 -acetamidoadamantan-l-one Following the procedure of Example 12, above, N- methyl-1-acetamidoadamantan-4a-ol was oxidized to give N-methyl-l-acetamidoadamantan 4 one, M.P. 119- 120 C.

Vc=o 1740; VN C=O 164:0 111 Nujol In the same manner following the procedure of Examples 12, 13 and 14 but substituting other compound of Formula ILA as starting materials in place of l-acetamidoadamantan-4a-ol is productive of the corresponding l-amidoadamantan 4 ones of Formula IVA, for example, using the other 1-amidoadamantan-4-ols prepared and listed in Example 1, above, there is respectively obtained:

1-formamidoadamantan-4-one, 1-benzamidoadamantan-4-one, 1-propionamidoadamantan-4-one 1-butyramidoadamantan-4-one, 1-valera.midoadamantan-4-one, 1-hexanamidoadamantan-4-one, 1-decanamidoadamantan-4-one, 1-dodecanamidoadamantan-4-one, l-cyclopropanecarboxamidoadamantan-4-one, 1-cyclohexanecarboxamidoadamantan-4-one, 1-toluamidoadamantan-4-one, 1-naphthamidoadamantant-one,

1- (p-ethylbenzamido) adamantan-4-one, 1-phenylacetamidoadamantan-4-one, and 1-stearamidoadamantan-4-one.

In the same manner other 4-ols and 4,6-diols can likewise be converted to the corresponding ketones, for example, N-methyl-1-cyclohexylcarboxamidoadamantan- 4a,6a-diol to N-methyl-1-cyclohexylcarboxamidoadamantan-4,6-dione, N phenylacetamidoadamantan-4a,6a.-diol to 1-phenylacetamidoadamantan 4,6 dione, 4oz,6oc-dl-hydroxy N 1 adamantanephthalimide to 4,6-dioxo-N-1- adamantanephthalimide, 4a,6a dihydroxy-N-l-adamantanephthalimidine to 4,6-dioxo-N-l-adamantanephthalimidine, 1-acetamidoadamantan-4 8-01 to l-acetamidoadamantan-4-one, and the like.

EXAMPLE 16 1-acetamid0aaamantan-4-0ne oxime A mixture of 1.25 g. of 1-acetamidoadamantan-4-one, 10.0 ml. of ethanol, 10.0 ml. of pyridine and 1.25 g. of hydroxy amine hydrochloride was heated at reflux for two hours. The mixture was then concentrated to dryness and the residue thus obtained was stirred with 5.0 m1. of water, chilled, and the solid product recovered by filtration, washed with 5 ml. of cold water and dried giving 1-acetamidoadamantan-4-one oxime, M.P. 197 198 C.

Analysis.-Calcd. for C H N O (percent): C, 64.84; H, 8.16; N, 12.61. Found (percent): C, 64.53; H, 8.11; N, 12.55.

In the same manner following the procedure of Example 16 but substituting as starting material-other 1- amidoadamantan-4-ones of Formulae IVA, VA or IXA, for example, those prepared and listed in the foregoing examples, in place of 1-acetamidoadamantan-4-one is productive of the corresponding oxime derivatives, for example, N-methyl-1-benzamidoadamantan-4,6-diones to N-methyl-1-benzamidoadamantan-4,6-dione dioxime hydrate, M.P. 250 C. (dec.).

AnalysiS.-Calcd. for C18H21N3O3'H2O (percent): C, 62.59; H, 6.71; N, 12.17. Found (percent): C, 62.85; H, 6.65; N, 12.10.

Likewise, other carbonyl derivatives of these compounds can also be prepared, for example, N-methyl-lbenzamidoadamantan-4,6-dione was reacted with semicarbazide hydrochloride in the presence of a base to EXAMPLE 17 1-amin0adamuntan-4a-ol hydrochloride A mixture of 4.0 g. of l-acetamidoadamantan-4a-0l, 160 ml. of ethylene glycol, and 16 g. of sodium hydroxide pellets was heated at reflux for five hours. After cooling and dilution with 200 ml. of water, the solution was extracted continuously with ether for eight hours and the extract dried over sodium sulfate and potassium hydroxide.

The ether can be removed by evaporation or distillation to obtain 1-arninoadamantan-4m-ol, recrystallized from ether, M.P. 248250 C. in a sealed tube (oil bath).

The dried ether extract was treated with ethereal hydrogen chloride to precipitate the amine salt; yield, 2.60 g. of 1-aminoadamantan-4a-ol hydrochloride, M.P. 300 (dec.).

AnaZysis.-Calcd. for CloHl'INO'HCl (percent): C, 58.96; H, 8.90; N, 6.88; Cl, 17.41. Found (percent): C, 58.79; H, 8.82; N, 6.73; Cl, 17.32.

In the same manner substituting l-acetamidoadamantan-4-one as starting material in Example 17 in place of 1-acetamidoadamantan-4a-ol is productive of l-aminoadamantan-4-one and the hydrochloride thereof.

EXAMPLE 18 1-amin0adamantan-3-0l and I-amz'noadamantan-S-ol hydrochloride A mixture of 300 mg. of 1-acetamidoadamantan-3-ol and 20 m1. of aqueous sodium hydroxide solution was heated at reflux for 22 hours. The mixture was diluted with 10 ml. of water and extracted several times with ether. The ether extract was dried over potassium hydroxide and the solvent removed to give 220 mg. of crystalline l-arninoadamantan-3-ol, a sample was recrystallized from ether-hexane, M.P. 267 C. in a sealed tube (oil bath).

A 100 mg. portion of the 1-aminoadamantau-3-ol thus obtained was dissolved in 50 ml. of ether and treated with ethereal hydrogen chloride to precipitate the hydrochloride salt which was recovered by filtration and recrystallized from methanol-methyl ethyl ketone to give laminoadamantan-Ei-ol hydrochloride, -M.P. 300 C.

Analysis.-Calcd. for C H NOCl (percent): C, 58.96; H, 8.90; N, 6.80. Found (percent): C, 59.07; H, 9.05; N, 7.21.

Similarly, following the procedures of Examples 17 and 18, above, other l-amidoadamantanes of Formulae IIA, IVA and HB can be converted to the corresponding l-aminoadamantanes of Formulae IIIA, VA and IIIB, respectively, and the hydrochloride acid addition salts thereof.

In the same manner following the procedures of Examples 17 and 18, other pharmacologically acceptable acids, such as those hereinbefore named, can be used in place of hydrogen chloride to obtain the corresponding acid addition salts of 1-aminoadamantan-4a-ol, l-aminoadamantan-4-one and 1-amin0adamantan-3-ol.

EXAMPLE 19 V I-(ethylamino)adamantan-4a-0l hydrochloride 7 To a mixture of 1.0g. of 1-acetamindoadamantan-4u-ol,

30 ml. of dihydropyran and 30 ml. of tetrahydrofuran was added two drops of concentrated hydrochloric acid. The mixture was allowed to stand at room temperature for about 96 hours. Thin layer chromatography at intervals indicated that it took this long for the reaction to go to completion. The solution was dried over sodium hydroxide and the solvent removed under reduced pressure to give a yellow oil.

The oil thus obtained was dissolved in 50 m1. of tetrahydrofuran, added to a stirred mixture of 2.0 g. of lithium aluminum hydride in 50 ml. of ether and heated at reflux for minutes. The mixture was then chilled and treated cautiously with 15 ml. of water, diluted with ether and filtered. The filtrate was dried over magnesium sulfate and concentrated to an oil. The oil was dissolved in about 50 ml. of ethanol, and 5.0 m1. of water and 2.0 mlpof concentrated HCl were added. The mixture was then heated at reflux for 30 minutes. After making basic with 50% sodium hydroxide solution, the mixture was concentrated in vacuo, diluted with water, and extracted with ether. The ether solution was dried over magnesium sulfate and the insoluble salt of the amine separated as anoil by adding ethereal HCl. The oil thus obtained was crystallized from methanolacetone; yield, 0.355 g. of l-(ethylamino) adamantan-4u-ol hydrochloride, M.P. 257-260 C.

Analysis.Calcd. for C H NO'HCl (percent): C, 62.18; H, 9.57; N, 6.04; C1, 15.30. Found (percent); C, 61.57; H, 9.79; N, 6.37; Cl, 14.75.

In the same manner following the procedure of Example 19', but substituting as starting material l-acetamidoadamantan-3-ol, in place of 1-acetamindoadamantan-4a- 01, is productive of l-(ethylamino)adamantan-3-ol hydrochloride.

Similarly, following the procedure of Example 19 the other l-amidoadamantanes of Formulae IIA and HE can be reduced to obtain the corresponding l-aminoadamantane hydrochlorides of Formulae VIFIA and VIB, respectively, for example, using the l-arnidoadamantan-Ziand 4-ols prepared and listed in the last paragraph of Example 1, such as:

1-formamidoadamantan-4a-ol, 1-formamidoadamantan-3-01, l-benzamidoadamantan-4a-ol, 1-benzamidoadamantan-3-ol,

l-propion amidoadamantan-4a-ol, 1-propionamidoadamantan-3-ol, 1-butyramidoadamantan-4u-ol, 1-butyramid0adamantan-3-ol, 1-hexanamidoadamantan-4a-ol, 1-hexanamidoadamantan-3-ol, 1-dodecanamidoadamantanla-ol, 1-dodecanamidoadamantan-3-ol, 1-cyclohexanecarboxamidoadamantau-4u-ol, 1-cyclohexanecarboxamidoadamantan-3-ol, 1-phenylacetamidoadamantan-4a-ol, l-phenylacetamidoadamantan-S-ol, 1-stearamidoadamantan-4a-ol, 1-stearamidoadamantan-3-ol,

and the like, there is respectively obtained and the like.

EXAMPLE 20 1- ethylamino adamantan-4a-0l One gram of 1-(ethylamino)adamantan-4u-ol hydrochloride and 20 ml. of aqueous sodium, hydroxide solution is stirred and the mixture is extracted several times with ether. The ether extracts are dried over sodium hydroxide pellets and the solvent removed to obtain l-(ethylamino)adamantantu-ol.

In the same manner other acid addition salts of the compounds of Formulae VIIIA and VIB such as the hydrochlorides listed in Example 19, above, can be converted to the corresponding free amines of Formulae VIIIA and VIB, respectively.

EXAMPLE 21 1 -(ethylamino) adamantan-4-0ne A mixture of 1.0 gram of l-(ethylamino)adamantan- 411-01, 60 ml. of toluene, ml. of cyclohexanone, and 2.0 g. of aluminum isopropoxide is distilled to remove 10 ml. of solvent and then heated at reflux for 60 minutes. The mixture is cooled and poured onto an ice-mixture containing excess hydrochloric acid. The mixture is stirred and the layers are separated. The aqueous layer is extracted several times with ether. The aqueous layer is then made basic by the addition of sodium hydroxide solution and the resulting gelatinous mixture is exhaustively extracted with ether; this ether extract is dried over potassium hydroxide and the solvent removed to leave a residue of 1-(ethylamino)adamantan-4-one which can be recrystallized, e.g., from ether-hexane.

In the same manner following the procedure of Ex- .ample 21, other free amines of Formula VIIA can be substituted as starting material in place of l-(ethylamino)- adamantan-4-ol, for example,

l- (methylamino) adamantan-4a-ol,

l- (benzylamino adamantan-4a-ol,

l- (propylamino adamantan-4a-ol,

l- (butylamino adamantan-4a-ol,

1- (hexylamino adamantan-4a-ol,

1- (cyclohexylmethyl)amino] adamantan-4u-ol, lphenethylamino adamantan-4u-ol,

ldodecylamino adamantan-4a-ol,

l- (octadecylamino adamantan-4a-ol,

and the like, there is obtained lmethylamino adamantan-4-one,

1- (benzylamino adamantan-4-one,

1- (propylamino) adamantan-4-one,

1- (butylamino adamantan-4-one,

l- (hex'ylamino adamantan-4-one,

1-[ (cyclohexylmethyl amino] adamantanl-one, 1- (phenethylamino adamantan-4-one,

1- (dodecylamino adamantan-4-one,

l- (octadecylamino) adamantan-4-one,

respectively, and the like.

EXAMPLE 22 I-(ethylamino)adamaman-4-0ne hydrochloride salts of the compounds of Formulae VIIIA, IXA and VIB.

EXAMPLE 23 1-acetamidoadamantan-4-0l acetate A mixture of 500 mg. of 1-acetamidoadamantan-4a-ol, 5 ml. of pyridine, and 1 ml. of acetic anhydride is stirred at room temperature (about 25 C.) overnight. The excess anhydride is then hydrolyzed by the addition of ice and water and the product is extracted with methylene chloride. The extract is Washed With dilute acid, dilute sodium bicarbonate, water, dried and concentrated in vacuo to give 1-acetamidoadamantan-4-ol acetate.

In the same manner substituting other acid anhydrides or acid halides of organic carboxylic acids, among which are hydrocarbon carboxylic acids of from 1 to 18 carbon atoms, inclusive, previously listed, is productive of the corresponding 1-acetamidoadamantan-4-ol acylate.

In the same manner following the procedure of Example 23 other compounds of Formula IIA for example, the 4-hydroxy compounds prepared and listed in Example 1, are converted to the corresponding 4-acylates by reacting the selected free 4-hydroxy compound with the appropriate acid anhydride or acid halide.

EXAMPLE 24 1-acetamid0adamantan-3-0l acetate A mixture of mg. of 1-acetamidoadamantan-3-01, 100 mg. of calcium carbonate powder and 3 ml. of acetic anhydride is stirred and heated at C. for a period of about 8 hours and then allowed to stand overnight. The mixture is diluted with water to hydrolyze the excess acetic anhydride. The product is extracted with methylene chloride and the extract washed with dilute sodium bicarbonate solution, water, dried and concentrated yielding l-acetamidoadamantan-3-ol acetate.

In the same manner substituting in place of acetic anhydride other acid anhydrides or acid halides or organic carboxylic acids, among which are the hydrocarbon carboxylic acids of from 1 to 18 carbon atoms, inclusive, previously listed, is productive of the corresponding 1- acetamidoadamantan-3-ol acylate.

In the same manner following the procedure of Example 24, other compounds of Formula IIB, for example the 3-hydroxy compounds prepared and listed in Example 1, are converted to the corresponding 3-acylates by reacting the selected free 3-hydroxy compound with the appropriate acid anhydride or acid halide.

ExAMPLE 25 1-aceramid0adamanran-4a and 413-0! To grams of 1-acetamidoadamantan-4-one dissolved in 25.0 ml. of methanol Was treated with 1.0 g. of sodium borohydride dissolved in 6.0 ml. of N/ 10 sodium hyroxide solution and the mixture was allowed to stand at room temperature for 18 hours. The mixture Was chilled at 0 C. and carefully treated dropwise with 50% acetic acid until a slight excess was present. The mixture was concentrated under reduced pressure and the residue was triturated with 50 ml. of tetrahydrofuran. The insoluble material was removed by filtration, the filtrate was chromatographed over a column of 100 g. of silica gel which had been prepared from a slurry of the silica gel in ethyl acetatehexane (5:1). The column was eluted in cuts of 50 ml. each with the Same solventmixture. The fractions were examined by thin layer chromatography and fractions 21- 28 (pool I) were combined as one isomer and fractions 41-79 (pool II) were combined as another isomer.

Pool I was recrystallized from methanol-benzene to yield 0.76 g. of 1acetamidoadamantan-4a-ol, M.P. 176- 177 C. Infrared red analysis and the mixed melting point showed the product to be identical tothe l-acetamidoadamantan-4a-ol obtained by bioconversion.

Pool 11 was recrystallized from methanol-benzene to yield 0.72 g. of l-acetamidoadamantan-4fi-ol, M.P. 206- 207 C.

Analysis.-Calcd. for C H NO (percent): C, 68.86; H, 9.15; N, 6.69. Found (percent): C, 68.90; H, 9.17; N, 6.53.

In the same manner following the procedure of Example 25, other compounds of Formulae IVA and VA can likewise selectively be reduced at the 4- and 4,6-positions to obtain a mixture of the corresponding and p-isomeric forms thereof, which can be separated by chromatography, for example, N-methyl-1-benzamidoadamantan,4,6-dione to N-methyl-1-benzamidoadamantan-4u,6a-diol, N-methyl 1 benzamidoadamantan 45,6;8-diol and N-methyl-lbenzarnidoadamantan-4a,6fi-diol; N-methyl-l-benzamidoadamantan 4 one to N-methyl-l-benzamidoadamantan- 4a 01 and N methyl-1-benzamidoadamantan-4p-ol; N- methyl-l-acetamidoadamantan-4-one to N-methyl-l-acetamidoadamantan 4a 01 and N methyl-l-acetamidoadamantan-4p-ol; and the like.

EXAMPLE 26 N benzyl-N-methyl-I-adamarztanamine-4a,6a-diol hydrochloride Four grams of N-methyl-l-benzamidoadamantan-4a,6adiol was reduced with an ether mixture of 4.0 g. of lithium aluminum hydride. The low solubility of this material made it necessary to carry out the reaction in such a manner that warm ether was continuously extracting the starting material into the refluxing ether-hydride mixture. The mixture was then cooled to 0 C., treated with about 30 m1. of water, diluted with ether, filtered and dried over magnesium sulfate. The drying agent was removed and ethereal hydrogen chloride was added to precipitated and hydrochloride salt, which was recrystallized from methanolmethyl ethyl ketone to give 3.0 g. of N-benzyl-N-methyl 1 adamantanamine 4a,6a diol hydrochlirode, M.P. 267-269 C.

Analysis.-Calcd. for C H NO C1 (percent): C, 66.75; H, 8.09; N, 4.33; Cl, 10.95. Found (percent): C, 66.71; H, 8.34; N, 4.36; Cl, 11.17.

EXAMPLE 27 N -benzy l-N-m ethyl-1 -adamantanam-ine-4 a-Ol Four grams of N-methyl-1-benzamidoadamantan-4a-ol in 150 ml. of dry tetrahydrofuran was added with stirring to a mixture of 3.0 g. of lithium aluminum hydride in 100 m1. of anhydrous ether. The mixture was heated at reflux for 150 minutes; a cold bath was applied, and 20 ml. of water was added with caution and stirring was continued for 30 minutes. The mixture was filtered and the insoluble material was washed Well With ether. The filtrate and wash was dried over magnesium sulfate and the solvent removed to give 3.36 g. of N-benzyl-N-methyl-ladamantanamine-4a-ol; a sample was recrystallized from ether-hexane for analysis, M.P. l19-120 C.

Analysis.Calcd. for C H NO (percent): C, 79.66; H, 9.29; N, 5.16. Found (percent): C, 79.44; H, 9.10; N, 5.07.

. EXAMPLE 28 N-methyl-I-adamantanamine-4a-ol and the hydrochloride Three grams of N-benzyl-N-methyl-l-adamantanamine- 4a-o1 was dissolved in 60 ml. of ethanol. One-half gram of palladium on carbon catalyst was added and the mixture was shaken with hydrogen (42 p.s.i.g.) for 150 minutes. The mixture was freed of catalyst and concentrated to dryness under reduced pressure to a solid residue. A 1.0 g. sample was recrystallized from ether to give N-methyl-l-adamantanamine-4u-ol, M.P. 141-l42 C.

Analysis.-Calcd. for C H NO (percent): C, 72.88; H, 10.57; N, 7.73. Found (percent): C, 72.82; H, 10.38; N, 7.49. I

The remainder of the residue was dissolved in ether and treated with ethereal hydrogen chloride and the resulting amine salt was recovered by filtration and washed with ether to give 1.26 of N-methyl-1-adamantanamine-4a-ol 24 hydrochlirode. An analytical sample was recrystalized from methanol-acetone, M.P. 220-221 C.

Analysis.Ca1cd. for C H NOCI (percent): C, 60.67; H, 9.26; N, 6.43; Cl, 16.29. Found (percent): C, 60.54; H, 9.50; N, 6.42; (:1, 16.42.

EXAMPLE 29 N-methyl-1-adamuntanamine-4u,6a-diol and the hydrochloride salt A mixture of 4 g. of N-benzyl-N-methyl-l-adamantanamine-4a,6a-diol is dissolved in -60 ml. of ethanol and treated with 0.5 g. of 10% palladium on carbon shaken with hydrogen (40 p.s.i.g.) for 3 hours. The catalyst is removed by filtration and the filtrate is evaporated to dryness under reduced pressure to give N-methyl-l-adamantanmine-4a,6a-diol, as a white solid, which is further purified by recrystallization from ether.

The hydrochloride salt is prepared by dissolving the free base in ether and adding an ether solution containing one equivalent of hydrogen chloride. The insoluble salt is recovered by filtration and recrystallized from methanolacetone as a white crystalline solid.

EXAMPLE 30 1 -formam idoadamantaniu-ol A solution of 3.5 g. of l-adamantanaminelot-ol in l l. of ether was treated with a slight excess of 98% formic. acid. The resulting precipitate of formate salt was recovered by filtration and Washed with ether; yield 3.60 g. of l-adamantanaminelm-ol formate, M.P. 238-239 C.

One gram of 1-adamantanamine-4u-ol formate was heated at 270 C. for 2 minutes and cooled. The residue was taken up in a small volume of ethyl acetate and chromatographed over a column prepared from a slurry of 100 g. of silica gel and ethyl acetate saturated with water. The column was eluted with the same solvent in fractions of 50 ml. each. Product fractions containing 1-formarnidoadamantan-4a-ol were determined by infrared inspection of the residues (0.58 g.). A sample of the residues for analysis was recrystallized from methanol-benzene to give l-formamidoadamantan-4a-ol, M.P. 141- 142 C.

Analysis.-Calcd. for C11H17N0'2 (percent): C, 67.66; H, 8.78; N, 7.17. Found (percent): C, 67.52; H, 8.79; N, 7.42.

EXAMPLE 31 N-methyl-I-adamantanamine-4ot-ol hydrochloride A mixture of 0.5 g. of 1formanridoadamantan-M-ol, 2.0 ml. of pyridine, and 1.0 ml. of acetic anhydride was allowed to stand at 25 C. for 16 hours. The mixture was diluted with water, extracted with methylene chloride. The extract was Washed with dilute sulfuric acid, water, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was taken up in 25 ml. of anhydrous tetrahydrofuran and added with stirring to a mixture of 0.5 g. of lithium aluminum hydride in 25 ml. of anhydrous ether. The mixture was heated at reflux for 2 hours, and chilled at 0 C. during the addition of 5.0 m1. of water. The mixture was filtered, the solids were washed well with ether, and the filtrate and wash'was dried over magnesium sulfate. The solution was freed of drying agent and treated with a slight excess of ethereal hydrogen chloride. The N-methyl-l-adamantanamine-4a-ol hydrochloride was recovered by filtration and recrystallized from methanol-acetone, M.P. 219-220" C. I

EXAMPLE 32 N-methyl-I-benzamidoadamantan-4a,6a-diol diacetate The N-methyl-l-benzamidoadamantan-4a,6oz-dio1 (0.5 g.), pyridine (5.0 ml.), and acetic anhydride (2.0 ml.) was mixed and warmed to dissolve the reactant and 8.1- lowed to stand at room temperature for 17 hours. The

mixture was poured onto ice and stirred for several min- 25 utes. The product was recovered by filtration, washed with water, and recrystallized from aqueous acetone to give N-methyl 1 benzamidoada-mantan-4a,6a-diol diacetate, M.P. 141 142 c.

Analysis.-Calcd. for C22H27NO5 (percent): C, 68.55; H, 7.06; N, 3.63. Found (percent): C, 68.88; H, 7.35; N,

EXAMPLE 33 N -methyl-1 -benzzz midoadamantan-4 a,6 a-aiol cyclic sulfite One-half gram of diol was treated with 1.0 ml. of thionyl chloride; immediate heat of reaction was noted and after 15 minutes the excess reagent was removed under reduced pressure. The residue was chromatographed over 100 g. of Florisil by the gradient method, placing the material on the column with methylene chloride and eluting n fractions of 110 ml. each, with 4 l. of solvent, Skellysolve B containing increasing proportions of acetone from -40%. Fractions 13-16 contained 0.35 g. of product which was recrystallized from ether-Skellysolve B as white needles of N-methyl-1-benzamidoadamantan-4a,6a-diol cyclic sulfite, M.'P. 172-173 C.

Analysis.-Calcd. for C- H NO S (percent): C, 62.22; H, 6.09; N, 4.03; S, 9.23. Found (percent): C, 62.28; H, 5.64; N, 3.73; S, 9.21.

We claim:

1. The process for oxygenating a compound of the formula:

wherein R is hydrogen, an alkyl radical of 1 to 18 carbon atoms, inclusive, an aralkyl radical of 7 to 13 carbon atoms, inclusive, an aryl radical of 6 to 12 carbon atoms, inclusive, or a cycloalkyl radical of to 15 carbon atoms, inclusive, Z is the acyl radical of a monobasic hydrocarbon carboxylic acid of 1 to 18 carbon atoms, inclusive, which comprises subjecting said compound to the oxygenating activity of Sporotrichum sulfurescens, Rhizopus arrhizus or Curvularia lunata.

2. The process of cclaim 1, wherein the oxygenation is carried out under submerged aerobic fermentation conditions and the fermentation is continued until a substantial amount of oxygenated products is produced.

3. The process of claim 1, wherein the oxygenation is carried out under submerged fermentation conditions; the fermentation is continued until a substantial amount of oxygenated products is produced and the oxygenated products are recovered from the fermentation medium.

4. The process for the production of oxygenated compounds of the formulae:

and

wherein Z is the acyl radical of a monobasic hydrocarbon carboxylic acid of 1 to 18 carbon atoms, inclusive, R is hydrogen, an alkyl radical of 1 to 18 carbon atoms, inclusive, an aralkyl radical of 7 to 13 carbon atoms, inclusive, an aryl radical of 6 to 12 carbon atoms, inclusive, or a cycloalkyl radical of 5 to 15 carbon atoms, inclusive,

26 and X is hydrogen or hydroxy, which comprises subjecting a compound of the formula v wherein R, X and Z have the meanings given above, to the oxygenating activity of Sporotrichum sulfurescens, Rhizopus arrhizus or Curvularia lunata.

5. The process of claim 4, wherein the oxygenation is carried out under submerged fermentation conditions and the fermentation is continued until a substantial amount of oxygenated products is produced.

6. The process of claim 4, wherein the oxygenation is carried out under submerged fermentation conditions; the fermentation is continued until a substantial amount of oxygenated products is produced and the oxygenated products are recovered from the fermentation medium.

7. The process of claim 4, wherein l-acetamidoadamantane is subjected to the oxygenating activity of Spamtrichum sulfurescens in an aqueous nutrient medium under aerobic fermentation conditions to obtain l-acetamidoadamantan-4a-ol and 1-acetamidoadamantan-3-ol.

8. The process of claim 4, wherein l-acetamidoadamantane is subjected to the oxygenating activity of Rhizopus arrhizus in an aqueous nutrient medium under aerobic fermentation conditions to obtain 1-acetamidoadamantan- 411-0] and 1-acetamidoadamantan-3-ol.

9. The process of claim 4, wherein l-acetamidoadamantane is subjected to the oxygenating activity of Curvularia lunata in an aqueous nutrient medium under aerobic fermentation conditions to obtain 1-acetamidoadamantan-4a- 01 and 1-acetamidoadamantan-3-o1.

10. The process of claim 4, wherein l-benzamidoadamantane is subjected to the oxygenating activity of Sporatrichum sulfurescens in an aqueous nutrient medium under aerobic fermentation conditions toobtain l-benzamidoadamantan-4a-ol and 1-benzamidoadamantan-3-ol.

11. The process of claim 4, wherein N-methyl-l-benzamidoada-mantane is subjected to the oxygenating activity of Sporozrichum sulfurescens in an aqueous nutrient medium under aerobic fermentation conditions to obtain N-methyl-1-benzamidoadamantan-4a-ol and N-methyl-lbenzamidoadamantan-4a,6a-diol.

12. The process of claim 4, wherein N-methyl-1-benzamidoadamantan-4a-ol is subjected to the oxygenating activity of Sporolrichum sulfurescens in an aqueous nutrient medium under aerobic fermentation conditions to obtain N-methyl-1-benzamidoadamantan-4a,6a-diol.

13. The process of claim 4, wherein N-methyl-l-acetamidoadamantane is subjected to the oxygenating activity of Sporotrichum sulfurescens in an aqueous nutrient medium under aerobic fermentation conditions to obtain N-methyl-1-acetamidoadamantan-4u-ol and N-methyl-lacetamidoadamantan-3-ol.

14. The process of claim 4, wherein N-methyl-1-cyclo hexylcarboxamidoadamantane is subjected to the oxygenating activity of Sporotrichum sulfurescens in an aqueous nutrient medium under aerobic fermentation conditions to obtain N-methyl-l-cyclohexylcarboxamidoadamantan-4a- 01 and N-methyl-l-cyclohexylcarboxamidoadamantan-4a, 6a-di01.

15. The process of claim 4, wherein l-phenylacetamidoadamantane is subjected to the oxygenating activity of Sporotrichum sulfurescens in an aqueous nutrient medium under aerobic fermentation conditions to obtain l-phenylacetamidoadamantan-4u-ol and l-phenylacetamidoadamantan-4a,6a-diol.

16. The process of claim 4, wherein N-l-adamantanephthalimide is subjected to the oxygenating activity of Sporotrichum sulfurescens in an aqueous nutrient medium t References Cited under aerobicfermentation conditions to obtain'4a-hyi droXy-N-lv-adamantanephthalimide and 4a,6a-dihydroxy- UNITE-D STATES PATENTS N-rl-adamantanephthalimide. 1 3,281,330 10/1966 Fonken et a] 195-51 17. The process which comprises subjecting N-l-ada- 5 3, 4/1970 Follken et l9551 mantanephthalimidine to the oxygenating activity of e Sporotrichum sulfurescens in an aqueous nutrient medium TANENHOLTZ Pnmary Examiner under aerobic fermentation conditions to obtain 4a-hydroxy N 1 adamantanephthalimidine and 4a,6cc-dihydroxy-N-ladamantanephthalimidine. 10 1.9529; 2605S8, 559, 561, 563, 570.9, 326, 488 

